Biological availability of pharmaceutical substances taken perorally depends on the extent to which the pharmaceutically active substance is absorbed from the intestinal environment across the intestinal mucosa. Hydrophobic pharmaceutical substances are generally poorly absorbed from the intestinal environment, inter alia because of their poor solubility and/or dispersibility in water.
The biological availability of pharmaceutical substances taken perorally is furthermore greatly dependent on their susceptibility to the so-called first pass effect Substances absorbed from the intestine, before being distributed throughout the body, have to pass the liver first where they may be metabolized immediately. This first pass effect is dependent on the substance. In the case of cannabinoids, examples are known in which more than 90% of the ingested dose is removed from the blood stream during the first pass.
Hence, ingestion or peroral administration of cannabinoids generally results in poor bioavailability.
Accordingly, over the years much effort has been put in the development of pharmaceutical delivery systems for transmucosal administration, especially buccal and sublingual administration of cannabinoids.
For transmucosal administration, it is important that the substance is rapidly released from the delivery system into the aqueous environment covering the mucosal surface so that it can be absorbed across said mucosal tissue. Especially in case a pharmaceutically active substance is poorly water-soluble or water-dispersible, it is a major challenge to formulate a delivery system that will achieve fast release of the pharmaceutically active substance in the fluid surrounding the mucosa so as to enable effective absorption of the pharmaceutically active substance by the mucosal tissue.
WO 2008/033024 A2 describes dosage units for sublingual, buccal or oral administration of water-insoluble pharmaceutically active substances. Example 1 describes the preparation of a monophasic microgranulate comprising Δ-9-tetrahydrocannabinol, and sucrose monolaurate in a weight ratio of 1:15 using a dry granulation process. Example 3 of this patent application describes the manufacture of a tabletting powder for direct compression using 50 g of the microgranulate obtained from Example 1 and 17 g of other components including 5 g of lactose and the compression to 7 mm tablets with a total weight of 60 mg. This patent application does not describe peroral administration.
WO 02/064109 A2 describes a pharmaceutical formulation for use in administration of a lipophilic medicament via a mucosal surface, which formulation comprises at least one lipophilic medicament and at least one self emulsifying agent, wherein the formulation, upon hydration, forms an emulsion containing the lipophilic medicament which is capable of adhering to a mucosal surface and allowing controlled release of the medicament. Also described are pharmaceutical formulations in the form of a gel or a compressed tablet for administration of a lipophilic medicament via the sublingual and/or buccal mucosa, wherein the tablet or gel, upon contact with saliva, forms an emulsion containing the lipophilic medicament that adheres reversibly to the sublingual and/or buccal mucosa. Example 6 of the patent application describes the preparation of a tablet for buccal or sublingual administration by dissolving glyceryl monostearate, polysorbate 80, ascorbyl palmitate and α-tocopherol and THC in alcohol, spraying the alcoholic solution onto a powder mix consisting of lactose and soluble starch, evaporating the alcohol, dusting the resulting granulate with talc and compressing to a target tablet weight of 101 mg. WO 02/064109 A2 aims at absorption via the sublingual and/or buccal mucosa since it is stated that medicaments taken perorally, i.e. taken by ingestion, are subject to the so-called first pass effect which would considerably limit the biological availability of the pharmaceutical substance.
WO 2005/004848 A1 relates to solid dispersions comprising tacrolimus and solid surfactant having a hydrophile lipophile balance (HLB) value higher than or equal to about 7. Example 19 describes the preparation of the solid dispersion of tacrolimus. Tacrolimus (30 g) was dissolved in the mixture of ethanol (100 ml) and dichloromethane (50 ml). In the thus obtained solution, sucrose fatty acid ester (HLB=9, 90 g) was dispersed as the drug carrier. The solution was sprayed on lactose (300 g) that was fluidized in a fluid bed granulator, and then dried.
In spite of the attempts to develop suitable buccal or sublingual transmucosal delivery systems, peroral administration is still generally seen as a more convenient mode of administration.
It is therefore an object of the present invention to provide oral dosage units for peroral delivery of cannabinoid with improved bioavailability.